NM_000314.8(PTEN):c.518G>A (p.Arg173His) AND PTEN hamartoma tumor syndrome

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Dec 9, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000490595.17

Allele description [Variation Report for NM_000314.8(PTEN):c.518G>A (p.Arg173His)]

NM_000314.8(PTEN):c.518G>A (p.Arg173His)

Gene:

PTEN:phosphatase and tensin homolog [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q23.31

Genomic location:

Preferred name:

NM_000314.8(PTEN):c.518G>A (p.Arg173His)

HGVS:

NC_000010.11:g.87952143G>A
NG_007466.2:g.93705G>A
NM_000314.8:c.518G>AMANE SELECT
NM_001304717.5:c.1037G>A
NM_001304718.2:c.-74G>A
NP_000305.3:p.Arg173His
NP_001291646.4:p.Arg346His
LRG_311t1:c.518G>A
LRG_311:g.93705G>A
NC_000010.10:g.89711900G>A
NM_000314.4:c.518G>A
NM_000314.6:c.518G>A

Protein change:

R173H

Links:

dbSNP: rs121913294

NCBI 1000 Genomes Browser:

rs121913294

Molecular consequence:

NM_001304718.2:c.-74G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000314.8:c.518G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001304717.5:c.1037G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: PTEN hamartoma tumor syndrome (PHTS)
Synonyms:: PTEN Hamartomatous Tumour Syndrome
Identifiers:: MONDO: MONDO:0017623; MeSH: D006223; MedGen: C1959582

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000579279	Herman Laboratory, Nationwide Children's Hospital	criteria provided, single submitter (Hansen-Kiss et al. (J Med Genet. 2017))	Pathogenic (Mar 1, 2017)	maternal, paternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000645595	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 9, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 19265751, 20533527, 23335809, 10866302, 17526800, 25669429, 28475857, 28492532
SCV000711962	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Oct 20, 2016)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 9619835, 20533527, 21828076, 19265751, 23633456, 10866302, 23335809, 17526800, 24033266
SCV004046133	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing
Caucasian	paternal	yes	1	not provided	not provided	1	yes	clinical testing
Caucasian	maternal	yes	2	not provided	not provided	2	yes	clinical testing

Citations

PubMed

A retrospective chart review of the features of PTEN hamartoma tumour syndrome in children.

Hansen-Kiss E, Beinkampen S, Adler B, Frazier T, Prior T, Erdman S, Eng C, Herman G.

J Med Genet. 2017 Jul;54(7):471-478. doi: 10.1136/jmedgenet-2016-104484. Epub 2017 May 19.

PubMed [citation]

PMID:: 28526761

KLLN epigenotype-phenotype associations in Cowden syndrome.

Nizialek EA, Mester JL, Dhiman VK, Smiraglia DJ, Eng C.

Eur J Hum Genet. 2015 Nov;23(11):1538-43. doi: 10.1038/ejhg.2015.8. Epub 2015 Feb 11.

PubMed [citation]

PMID:: 25669429
PMCID:: PMC4613489

See all PubMed Citations (14)

Details of each submission

From Herman Laboratory, Nationwide Children's Hospital, SCV000579279.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	1	not provided	yes	clinical testing	PubMed (1)
2	Caucasian	1	not provided	yes	clinical testing	PubMed (1)
3	Caucasian	1	not provided	yes	clinical testing	PubMed (1)

Description

Patient identified after PTEN diagnosis in sibling. Enlarged hyperemic thyroid gland and high TSH levels. Macrocephaly (+4 SD)

Macrocephaly (+5 SD)

Macrocephaly (+3.7 SD)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	1	Blood	not provided		1	not provided	not provided	not provided
2	maternal	yes	1	Blood	not provided		1	not provided	not provided	not provided
3	paternal	yes	1	Blood	not provided		1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000645595.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 173 of the PTEN protein (p.Arg173His). This variant is present in population databases (rs121913294, gnomAD 0.01%). This missense change has been observed in individuals with PTEN hamartoma tumor syndrome (PMID: 17526800, 19265751, 20533527, 23335809; Invitae). ClinVar contains an entry for this variant (Variation ID: 376032). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTEN protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PTEN function (PMID: 10866302). This variant disrupts the p.Arg173 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10866302, 17526800, 25669429, 28475857). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000711962.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (9)

Description

The p.Arg173His variant has been reported in 4 individuals with clinical feature s of Cowden syndrome (Lachlan 2007, Mcbride 2010, Bubien 2013) and segregated wi th disease in 2 affected relatives from 2 different families (Lachlan 2007, Varg a 2004). In addition, it segregated with macrocephaly in 1 relative from a third family (McBride 2010). This variant has been identified in 1/10324 African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs121913294). This variant has been observed as a somatic mutation in t umors, including glioblastoma (Duerr 1998) and colorectal cancer (Day 2013). The p.Arg173His variant is associated with decreased protein activity in vitro (Han 2000, Rodriguez-Escudero 2011). However, these types of assays may not accurate ly represent biological function. In summary, although additional studies are re quired to fully establish its clinical significance, the p.Arg173His variant is likely pathogenic in an autosomal dominant manner.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		1	not provided	1	not provided

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV004046133.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant has been previously reported as a heterozygous change in patients with PTEN hamartoma tumor syndrome (PMID: 17526800, 19265751, 23335809, 20533527, 28526761). In vitro assays showed that this variant is associated with decreased phosphatase activity (PMID: 21828076, 10866302). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.001 % (2/251148) and thus is presumed to be rare. The c.518G>A (p.Arg173His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.518G>A (p.Arg173His) variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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